Deuterated momelotinib

ABSTRACT

The present invention in one embodiment provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, wherein the variables shown in Formula I are as defined in the specification.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national phase under 35 U.S.C. §371 of PCTInternational Application No. PCT/US2014/010760, filed Jan. 8, 2014,which claims the benefit of and priority to U.S. Provisional ApplicationNo. 61/750,802 filed on Jan. 9, 2013, the entire contents of theaforementioned applications are hereby incorporated by reference intheir entirety.

BACKGROUND OF THE INVENTION

Many current medicines suffer from poor absorption, distribution,metabolism and/or excretion (ADME) properties that prevent their wideruse or limit their use in certain indications. Poor ADME properties arealso a major reason for the failure of drug candidates in clinicaltrials. While formulation technologies and prodrug strategies can beemployed in some cases to improve certain ADME properties, theseapproaches often fail to address the underlying ADME problems that existfor many drugs and drug candidates. One such problem is rapid metabolismthat causes a number of drugs, which otherwise would be highly effectivein treating a disease, to be cleared too rapidly from the body. Apossible solution to rapid drug clearance is frequent or high dosing toattain a sufficiently high plasma level of drug. This, however,introduces a number of potential treatment problems such as poor patientcompliance with the dosing regimen, side effects that become more acutewith higher doses, and increased cost of treatment. A rapidlymetabolized drug may also expose patients to undesirable toxic orreactive metabolites.

Another ADME limitation that affects many medicines is the formation oftoxic or biologically reactive metabolites. As a result, some patientsreceiving the drug may experience toxicities, or the safe dosing of suchdrugs may be limited such that patients receive a suboptimal amount ofthe active agent. In certain cases, modifying dosing intervals orformulation approaches can help to reduce clinical adverse effects, butoften the formation of such undesirable metabolites is intrinsic to themetabolism of the compound.

In some select cases, a metabolic inhibitor will be co-administered witha drug that is cleared too rapidly. Such is the case with the proteaseinhibitor class of drugs that are used to treat HIV infection. The FDArecommends that these drugs be co-dosed with ritonavir, an inhibitor ofcytochrome P450 enzyme 3A4 (CYP3A4), the enzyme typically responsiblefor their metabolism (see Kempf, D. J. et al., Antimicrobial agents andchemotherapy, 1997, 41(3): 654-60). Ritonavir, however, causes adverseeffects and adds to the pill burden for HIV patients who must alreadytake a combination of different drugs. Similarly, the CYP2D6 inhibitorquinidine has been added to dextromethorphan for the purpose of reducingrapid CYP2D6 metabolism of dextromethorphan in a treatment ofpseudobulbar affect. Quinidine, however, has unwanted side effects thatgreatly limit its use in potential combination therapy (see Wang, L etal., Clinical Pharmacology and Therapeutics, 1994, 56(6 Pt 1): 659-67;and FDA label for quinidine at www.accessdata.fda.gov).

In general, combining drugs with cytochrome P450 inhibitors is not asatisfactory strategy for decreasing drug clearance. The inhibition of aCYP enzyme's activity can affect the metabolism and clearance of otherdrugs metabolized by that same enzyme. CYP inhibition can cause otherdrugs to accumulate in the body to toxic levels.

A potentially attractive strategy for improving a drug's metabolicproperties is deuterium modification. In this approach, one attempts toslow the CYP-mediated metabolism of a drug or to reduce the formation ofundesirable metabolites by replacing one or more hydrogen atoms withdeuterium atoms. Deuterium is a safe, stable, non-radioactive isotope ofhydrogen. Compared to hydrogen, deuterium forms stronger bonds withcarbon. In select cases, the increased bond strength imparted bydeuterium can positively impact the ADME properties of a drug, creatingthe potential for improved drug efficacy, safety, and/or tolerability.At the same time, because the size and shape of deuterium areessentially identical to those of hydrogen, replacement of hydrogen bydeuterium would not be expected to affect the biochemical potency andselectivity of the drug as compared to the original chemical entity thatcontains only hydrogen.

Over the past 35 years, the effects of deuterium substitution on therate of metabolism have been reported for a very small percentage ofapproved drugs (see, e.g., Blake, M I et al, J Pharm Sci, 1975,64:367-91; Foster, A B, Adv Drug Res 1985, 14:1-40 (“Foster”); Kushner,D J et al, Can J Physiol Pharmacol 1999, 79-88; Fisher, M B et al, CurrOpin Drug Discov Devel, 2006, 9:101-09 (“Fisher”)). The results havebeen variable and unpredictable. For some compounds deuteration causeddecreased metabolic clearance in vivo. For others, there was no changein metabolism. Still others demonstrated increased metabolic clearance.The variability in deuterium effects has also led experts to question ordismiss deuterium modification as a viable drug design strategy forinhibiting adverse metabolism (see Foster at p. 35 and Fisher at p.101).

The effects of deuterium modification on a drug's metabolic propertiesare not predictable even when deuterium atoms are incorporated at knownsites of metabolism. Only by actually preparing and testing a deuterateddrug can one determine if and how the rate of metabolism will differfrom that of its non-deuterated counterpart. See, for example, Fukuto etal. (J. Med. Chem. 1991, 34, 2871-76). Many drugs have multiple siteswhere metabolism is possible. The site(s) where deuterium substitutionis required and the extent of deuteration necessary to see an effect onmetabolism, if any, will be different for each drug.

CYT387, also known as momelotinib, and asN-(cyanomethyl)-4-[2-[4-(4-morpholinyl)phenylamino]pyrimidin-4-yl]benzamidedihydrochloride, is an inhibitor of Janus kinase 1 (JAK1) and Januskinase 2 (JAK2), currently being developed by YM Biosciences for thetreatment of chronic myeloproliferative neoplasms (MPNs). It is also inclinical trials for primary myelofibrosis, post-polycythemia vera, andpost-essential thrombocythemia.

Despite the beneficial properties of momelotinib, further advances inthe treatment of disorders that may be treated by an inhibitor of JAK1and JAK2 are desirable.

DETAILED DESCRIPTION OF THE INVENTION Definitions

The term “treat” means decrease, suppress, attenuate, diminish, arrest,or stabilize the development or progression of a disease (e.g., adisease or disorder delineated herein), lessen the severity of thedisease or improve the symptoms associated with the disease.

“Disease” means any condition or disorder that damages or interfereswith the normal function of a cell, tissue, or organ.

It will be recognized that some variation of natural isotopic abundanceoccurs in a synthesized compound depending upon the origin of chemicalmaterials used in the synthesis. Thus, a preparation of momelotinib willinherently contain small amounts of deuterated isotopologues. Theconcentration of naturally abundant stable hydrogen and carbon isotopes,notwithstanding this variation, is small and immaterial as compared tothe degree of stable isotopic substitution of compounds of thisinvention. See, for instance, Wada, E et al., Seikagaku, 1994, 66:15;Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998,119:725.

In the compounds of this invention any atom not specifically designatedas a particular isotope is meant to represent any stable isotope of thatatom. Unless otherwise stated, when a position is designatedspecifically as “H” or “hydrogen”, the position is understood to havehydrogen at its natural abundance isotopic composition. Also unlessotherwise stated, when a position is designated specifically as “D” or“deuterium”, the position is understood to have deuterium at anabundance that is at least 3000 times greater than the natural abundanceof deuterium, which is 0.015% (i.e., at least 45% incorporation ofdeuterium).

The term “isotopic enrichment factor” as used herein means the ratiobetween the isotopic abundance and the natural abundance of a specifiedisotope.

In other embodiments, a compound of this invention has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium), at least 5500 (82.5%deuterium incorporation), at least 6000 (90% deuterium incorporation),at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97%deuterium incorporation), at least 6600 (99% deuterium incorporation),or at least 6633.3 (99.5% deuterium incorporation).

The term “isotopologue” refers to a species in which the chemicalstructure differs from a specific compound of this invention only in theisotopic composition thereof.

The term “compound,” when referring to a compound of this invention,refers to a collection of molecules having an identical chemicalstructure, except that there may be isotopic variation among theconstituent atoms of the molecules. Thus, it will be clear to those ofskill in the art that a compound represented by a particular chemicalstructure containing indicated deuterium atoms, will also contain lesseramounts of isotopologues having hydrogen atoms at one or more of thedesignated deuterium positions in that structure. The relative amount ofsuch isotopologues in a compound of this invention will depend upon anumber of factors including the isotopic purity of deuterated reagentsused to make the compound and the efficiency of incorporation ofdeuterium in the various synthesis steps used to prepare the compound.However, as set forth above the relative amount of such isotopologues intoto will be less than 55% of the compound. In other embodiments, therelative amount of such isotopologues in toto will be less than 50%,less than 47.5%, less than 40%, less than 32.5%, less than 25%, lessthan 17.5%, less than 10%, less than 5%, less than 3%, less than 1%, orless than 0.5% of the compound.

The invention also provides salts of the compounds of the invention.

A salt of a compound of this invention is formed between an acid and abasic group of the compound, such as an amino functional group, or abase and an acidic group of the compound, such as a carboxyl functionalgroup. According to another embodiment, the compound is apharmaceutically acceptable acid addition salt.

The term “pharmaceutically acceptable,” as used herein, refers to acomponent that is, within the scope of sound medical judgment, suitablefor use in contact with the tissues of humans and other mammals withoutundue toxicity, irritation, allergic response and the like, and arecommensurate with a reasonable benefit/risk ratio. A “pharmaceuticallyacceptable salt” means any non-toxic salt that, upon administration to arecipient, is capable of providing, either directly or indirectly, acompound of this invention. A “pharmaceutically acceptable counterion”is an ionic portion of a salt that is not toxic when released from thesalt upon administration to a recipient.

Acids commonly employed to form pharmaceutically acceptable saltsinclude inorganic acids such as hydrogen bisulfide, hydrochloric acid,hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, aswell as organic acids such as para-toluenesulfonic acid, salicylic acid,tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylicacid, fumaric acid, gluconic acid, glucuronic acid, formic acid,glutamic acid, methanesulfonic acid, ethanesulfonic acid,benzenesulfonic acid, lactic acid, oxalic acid, para-bromophenylsulfonicacid, carbonic acid, succinic acid, citric acid, benzoic acid and aceticacid, as well as related inorganic and organic acids. Suchpharmaceutically acceptable salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate,succinate, suberate, sebacate, fumarate, maleate, butyne-1,4-dioate,hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate,dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate,terephthalate, sulfonate, xylene sulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate,glycolate, maleate, tartrate, methanesulfonate, propanesulfonate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate and othersalts. In one embodiment, pharmaceutically acceptable acid additionsalts include those formed with mineral acids such as hydrochloric acidand hydrobromic acid, and especially those formed with organic acidssuch as maleic acid.

The pharmaceutically acceptable salt may also be a salt of a compound ofthe present invention and a base. Exemplary bases include, but are notlimited to, hydroxide of alkali metals including sodium, potassium, andlithium; hydroxides of alkaline earth metals such as calcium andmagnesium; hydroxides of other metals, such as aluminum and zinc;ammonia, organic amines such as unsubstituted or hydroxyl-substitutedmono-, di-, or tri-alkylamines, dicyclohexylamine; tributyl amine;pyridine; N-methylamine, N-ethylamine; diethylamine; triethylamine;mono-, bis-, or tris-(2-OH—(C₁-C₆)-alkylamine), such asN,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;N-methyl-D-glucamine; morpholine; thiomorpholine; piperidine;pyrrolidine; and amino acids such as arginine, lysine, and the like.

The compounds of the present invention (e.g., compounds of Formula I),may contain an asymmetric carbon atom, for example, as the result ofdeuterium substitution or otherwise. As such, compounds of thisinvention can exist as either individual enantiomers, or mixtures of thetwo enantiomers. Accordingly, a compound of the present invention mayexist as either a racemic mixture or a scalemic mixture, or asindividual respective stereoisomers that are substantially free fromanother possible stereoisomer. The term “substantially free of otherstereoisomers” as used herein means less than 25% of otherstereoisomers, preferably less than 10% of other stereoisomers, morepreferably less than 5% of other stereoisomers and most preferably lessthan 2% of other stereoisomers are present. Methods of obtaining orsynthesizing an individual enantiomer for a given compound are known inthe art and may be applied as practicable to final compounds or tostarting material or intermediates.

Unless otherwise indicated, when a disclosed compound is named ordepicted by a structure without specifying the stereochemistry and hasone or more chiral centers, it is understood to represent all possiblestereoisomers of the compound.

The term “stable compounds,” as used herein, refers to compounds whichpossess stability sufficient to allow for their manufacture and whichmaintain the integrity of the compound for a sufficient period of timeto be useful for the purposes detailed herein (e.g., formulation intotherapeutic products, intermediates for use in production of therapeuticcompounds, isolatable or storable intermediate compounds, treating adisease or condition responsive to therapeutic agents).

“D” and “d” both refer to deuterium. “d_(x-y)” refers to substitutionwith from x to y number of deuterium atoms. “Stereoisomer” refers toboth enantiomers and diastereomers. “Tert” and “t-” each refer totertiary. “US” refers to the United States of America.

A group is “substituted with” a substituent when one or more hydrogenatoms of the group are replaced with a corresponding number ofsubstituent atoms (if the substituent is an atom) or groups (if thesubstituent is a group). For example, “substituted with deuterium”refers to the replacement of one or more hydrogen atoms with acorresponding number of deuterium atoms.

Throughout this specification, a variable may be referred to generally(e.g., “each Y”) or may be referred to specifically (e.g., Y¹, Y², Y³,etc.). Unless otherwise indicated, when a variable is referred togenerally, it is meant to include all specific embodiments of thatparticular variable.

Therapeutic Compounds

The present invention in one embodiment provides a compound of FormulaI:

or a pharmaceutically acceptable salt thereof, wherein:Y¹, Y², Y³, Y⁴, Z¹, Z², Z³, Z⁴, W¹ and W² are each independentlyselected from hydrogen and deuterium;provided that if Y¹, Y², Y³, Y⁴, Z¹, Z², Z³, Z⁴, and W¹ are eachhydrogen, then W² is deuterium.

In one embodiment of Formula I, Y¹ and Y² are the same; Y³ and Y⁴ arethe same; Z¹ and Z² are the same; Z³ and Z⁴ are the same; and W¹ and W²are the same.

In one embodiment of Formula I, Y¹, Y² Y³ and Y⁴ are each hydrogen. Inone aspect of this embodiment, Z¹, Z², Z³ and Z⁴ are each hydrogen. Inanother aspect, Z¹, Z², Z³ and Z⁴ are each deuterium.

In one embodiment of Formula I, Y¹, Y² Y³ and Y⁴ are each deuterium. Inone aspect of this embodiment, Z¹, Z², Z³ and Z⁴ are each hydrogen. Inanother aspect, Z¹, Z², Z³ and Z⁴ are each deuterium.

In one embodiment of Formula I, W¹ and W² are each hydrogen. In anotherembodiment, W¹ and W² are each deuterium.

In one embodiment, the compound is a compound of Formula I selected fromany one of the compounds (Cmpd) set forth in Table 1 (below):

TABLE 1 Y¹ = Y² = Z¹ = Z² = Cmpd # Y³ = Y⁴ Z³ = Z⁴ W¹ = W² 101 H H D 102H D H 103 H D D 104 D H H 105 D H D 106 D D H 107 D D Dor a pharmaceutically acceptable salt thereof, wherein any atom notdesignated as deuterium in Formula I is present at its natural isotopicabundance.

In another set of embodiments, any atom not designated as deuterium inany of the embodiments, aspects, or examples set forth above is presentat its natural isotopic abundance.

The synthesis of compounds of Formula I may be readily achieved bysynthetic chemists of ordinary skill by reference to the ExemplarySynthesis and Examples disclosed herein. Relevant procedures andintermediates analogous to those in international patent publication WO2008/109943, may be employed utilizing corresponding deuterated andoptionally, other isotope-containing reagents and/or intermediates tosynthesize the compounds delineated herein, or invoking standardsynthetic protocols known in the art for introducing isotopic atoms to achemical structure.

Exemplary Synthesis

Compounds of Formula I may be prepared as outlined in Scheme 1 below.

As shown in Scheme 1, compound 1, described in patent publicationWO20081099443, is treated with 2 (prepared as disclosed in Scheme 2below) to give 3. Treatment of 3 with 4 as shown in Scheme 1 affords acompound of Formula I.

Examples of deuterated analogs of Formula I that may be prepared via theroute described in scheme I are depicted in Table 2 (below):

TABLE 2 Cmpd # Compound Structure 101

102

103

104

105

106

107

Appropriately deuterated intermediates 2 may be prepared in a manneranalogous to that disclosed in Kumar, D. et al Bioorg. Med. Chem. Lett.2012, 22, 4377-4385) as shown in Scheme 2 below.

Examples of deuterated intermediate 2 that may be prepared via the routedescribed in scheme 2 include the following:

Examples of deuterated morpholines that may be used as intermediates forthe preparation of the compound of Formula I include the following:

Morpholine A may be prepared, for example, as disclosed in Scheme 1 ofinternational patent publication WO2009154754. Morpholine B may beprepared, for example, as disclosed in Scheme 3 of international patentpublication WO2009023233. Morpholine C is commercially available fromCDN Isotopes, Inc.

The preparation of the deuterated aminonitrile 4a (below), which may beused in Scheme 1, has been previously described in Felten, A. E. et alOrg. Lett. 2010, 12, 1916-1910.

Combinations of substituents and variables envisioned by this inventionare only those that result in the formation of stable compounds.

Compositions

The invention also provides pharmaceutical compositions comprising aneffective amount of a compound of Formula I (e.g., including any of theformulae herein), or a pharmaceutically acceptable salt of saidcompound; and a pharmaceutically acceptable carrier. The carrier(s) are“acceptable” in the sense of being compatible with the other ingredientsof the formulation and, in the case of a pharmaceutically acceptablecarrier, not deleterious to the recipient thereof in an amount used inthe medicament.

Pharmaceutically acceptable carriers, adjuvants and vehicles that may beused in the pharmaceutical compositions of this invention include, butare not limited to, ion exchangers, alumina, aluminum stearate,lecithin, serum proteins, such as human serum albumin, buffer substancessuch as phosphates, glycine, sorbic acid, potassium sorbate, partialglyceride mixtures of saturated vegetable fatty acids, water, salts orelectrolytes, such as protamine sulfate, disodium hydrogen phosphate,potassium hydrogen phosphate, sodium chloride, zinc salts, colloidalsilica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-basedsubstances, polyethylene glycol, sodium carboxymethylcellulose,polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers,polyethylene glycol and wool fat. If required, the solubility andbioavailability of the compounds of the present invention inpharmaceutical compositions may be enhanced by methods well-known in theart. One method includes the use of lipid excipients in the formulation.See “Oral Lipid-Based Formulations: Enhancing the Bioavailability ofPoorly Water-Soluble Drugs (Drugs and the Pharmaceutical Sciences),”David J. Hauss, ed. Informa Healthcare, 2007; and “Role of LipidExcipients in Modifying Oral and Parenteral Drug Delivery: BasicPrinciples and Biological Examples,” Kishor M. Wasan, ed.Wiley-Interscience, 2006.

Another known method of enhancing bioavailability is the use of anamorphous form of a compound of this invention optionally formulatedwith a poloxamer, such as LUTROL™ and PLURONIC™ (BASF Corporation), orblock copolymers of ethylene oxide and propylene oxide. See U.S. Pat.No. 7,014,866; and United States patent publications 20060094744 and20060079502.

The pharmaceutical compositions of the invention include those suitablefor oral, rectal, nasal, topical (including buccal and sublingual),vaginal or parenteral (including subcutaneous, intramuscular,intravenous and intradermal) administration. In certain embodiments, thecompound of the formulae herein is administered transdermally (e.g.,using a transdermal patch or iontophoretic techniques). Otherformulations may conveniently be presented in unit dosage form, e.g.,tablets, sustained release capsules, and in liposomes, and may beprepared by any methods well known in the art of pharmacy. See, forexample, Remington: The Science and Practice of Pharmacy, LippincottWilliams & Wilkins, Baltimore, Md. (20th ed. 2000).

Such preparative methods include the step of bringing into associationwith the molecule to be administered ingredients such as the carrierthat constitutes one or more accessory ingredients. In general, thecompositions are prepared by uniformly and intimately bringing intoassociation the active ingredients with liquid carriers, liposomes orfinely divided solid carriers, or both, and then, if necessary, shapingthe product.

In certain embodiments, the compound is administered orally.Compositions of the present invention suitable for oral administrationmay be presented as discrete units such as capsules, sachets, or tabletseach containing a predetermined amount of the active ingredient; apowder or granules; a solution or a suspension in an aqueous liquid or anon-aqueous liquid; an oil-in-water liquid emulsion; a water-in-oilliquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatincapsules can be useful for containing such suspensions, which maybeneficially increase the rate of compound absorption.

In the case of tablets for oral use, carriers that are commonly usedinclude lactose and corn starch. Lubricating agents, such as magnesiumstearate, are also typically added. For oral administration in a capsuleform, useful diluents include lactose and dried cornstarch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavoring and/or coloring agents may be added.

Compositions suitable for oral administration include lozengescomprising the ingredients in a flavored basis, usually sucrose andacacia or tragacanth; and pastilles comprising the active ingredient inan inert basis such as gelatin and glycerin, or sucrose and acacia.

Compositions suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which may contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which may include suspending agents and thickeningagents. The formulations may be presented in unit-dose or multi-dosecontainers, for example, sealed ampules and vials, and may be stored ina freeze dried (lyophilized) condition requiring only the addition ofthe sterile liquid carrier, for example water for injections,immediately prior to use. Extemporaneous injection solutions andsuspensions may be prepared from sterile powders, granules and tablets.

Such injection solutions may be in the form, for example, of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to techniques known in the art using suitabledispersing or wetting agents (such as, for example, Tween 80) andsuspending agents. The sterile injectable preparation may also be asterile injectable solution or suspension in a non-toxicparenterally-acceptable diluent or solvent, for example, as a solutionin 1,3-butanediol. Among the acceptable vehicles and solvents that maybe employed are mannitol, water, Ringer's solution and isotonic sodiumchloride solution. In addition, sterile, fixed oils are conventionallyemployed as a solvent or suspending medium. For this purpose, any blandfixed oil may be employed including synthetic mono- or diglycerides.Fatty acids, such as oleic acid and its glyceride derivatives are usefulin the preparation of injectables, as are naturalpharmaceutically-acceptable oils, such as olive oil or castor oil,especially in their polyoxyethylated versions. These oil solutions orsuspensions may also contain a long-chain alcohol diluent or dispersant.

The pharmaceutical compositions of this invention may be administered inthe form of suppositories for rectal administration. These compositionscan be prepared by mixing a compound of this invention with a suitablenon-irritating excipient which is solid at room temperature but liquidat the rectal temperature and therefore will melt in the rectum torelease the active components. Such materials include, but are notlimited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilizing or dispersing agents known inthe art. See, e.g.: Rabinowitz J D and Zaffaroni A C, U.S. Pat. No.6,803,031, assigned to Alexza Molecular Delivery Corporation.

Topical administration of the pharmaceutical compositions of thisinvention is especially useful when the desired treatment involves areasor organs readily accessible by topical application. For topicalapplication topically to the skin, the pharmaceutical composition shouldbe formulated with a suitable ointment containing the active componentssuspended or dissolved in a carrier. Carriers for topical administrationof the compounds of this invention include, but are not limited to,mineral oil, liquid petroleum, white petroleum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax, and water.Alternatively, the pharmaceutical composition can be formulated with asuitable lotion or cream containing the active compound suspended ordissolved in a carrier. Suitable carriers include, but are not limitedto, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esterswax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Thepharmaceutical compositions of this invention may also be topicallyapplied to the lower intestinal tract by rectal suppository formulationor in a suitable enema formulation. Topically-transdermal patches andiontophoretic administration are also included in this invention.

Application of the subject therapeutics may be local, so as to beadministered at the site of interest. Various techniques can be used forproviding the subject compositions at the site of interest, such asinjection, use of catheters, trocars, projectiles, pluronic gel, stents,sustained drug release polymers or other device which provides forinternal access.

Thus, according to yet another embodiment, the compounds of thisinvention may be incorporated into compositions for coating animplantable medical device, such as prostheses, artificial valves,vascular grafts, stents, or catheters. Suitable coatings and the generalpreparation of coated implantable devices are known in the art and areexemplified in U.S. Pat. Nos. 6,099,562; 5,886,026; and 5,304,121. Thecoatings are typically biocompatible polymeric materials such as ahydrogel polymer, polymethyldisiloxane, polycaprolactone, polyethyleneglycol, polylactic acid, ethylene vinyl acetate, and mixtures thereof.The coatings may optionally be further covered by a suitable topcoat offluorosilicone, polysaccharides, polyethylene glycol, phospholipids orcombinations thereof to impart controlled release characteristics in thecomposition. Coatings for invasive devices are to be included within thedefinition of pharmaceutically acceptable carrier, adjuvant or vehicle,as those terms are used herein.

According to another embodiment, the invention provides a method ofcoating an implantable medical device comprising the step of contactingsaid device with the coating composition described above. It will beobvious to those skilled in the art that the coating of the device willoccur prior to implantation into a mammal.

According to another embodiment, the invention provides a method ofimpregnating an implantable drug release device comprising the step ofcontacting said drug release device with a compound or composition ofthis invention. Implantable drug release devices include, but are notlimited to, biodegradable polymer capsules or bullets, non-degradable,diffusible polymer capsules and biodegradable polymer wafers.

According to another embodiment, the invention provides an implantablemedical device coated with a compound or a composition comprising acompound of this invention, such that said compound is therapeuticallyactive.

According to another embodiment, the invention provides an implantabledrug release device impregnated with or containing a compound or acomposition comprising a compound of this invention, such that saidcompound is released from said device and is therapeutically active.

Where an organ or tissue is accessible because of removal from thesubject, such organ or tissue may be bathed in a medium containing acomposition of this invention, a composition of this invention may bepainted onto the organ, or a composition of this invention may beapplied in any other convenient way.

In another embodiment, a composition of this invention further comprisesa second therapeutic agent. The second therapeutic agent may be selectedfrom any compound or therapeutic agent known to have or thatdemonstrates advantageous properties when administered with a compoundhaving the same mechanism of action as momelotinib. Such agents includethose indicated as being useful in combination with momelotinib.

Preferably, the second therapeutic agent is an agent useful in thetreatment or prevention of a disease or condition selected from chronicmyeloproliferative neoplasms (MPNs), primary myelofibrosis (PMF),post-polycythemia vera (PV) or post-essential thrombocythemia (ET).

In another embodiment, the invention provides separate dosage forms of acompound of this invention and one or more of any of the above-describedsecond therapeutic agents, wherein the compound and second therapeuticagent are associated with one another. The term “associated with oneanother” as used herein means that the separate dosage forms arepackaged together or otherwise attached to one another such that it isreadily apparent that the separate dosage forms are intended to be soldand administered together (within less than 24 hours of one another,consecutively or simultaneously).

In the pharmaceutical compositions of the invention, the compound of thepresent invention is present in an effective amount. As used herein, theterm “effective amount” refers to an amount which, when administered ina proper dosing regimen, is sufficient to treat the target disorder.

The interrelationship of dosages for animals and humans (based onmilligrams per meter squared of body surface) is described in Freireichet al., Cancer Chemother. Rep, 1966, 50: 219. Body surface area may beapproximately determined from height and weight of the subject. See,e.g., Scientific Tables, Geigy Pharmaceuticals, Ardsley, N.Y., 1970,537.

In one embodiment, an effective amount of a compound of this inventioncan range from 5 mg to 500 mg, such as 10 mg to 400 mg, such as 50 mg to300 mg, such as 100 mg to 200 mg, such as 150 mg, wherein any of theforegoing amounts may be administered once a day.

In one embodiment, an effective amount of a compound of this inventioncan range from 2.5 mg to 250 mg, such as 5 mg to 200 mg, such as 25 mgto 150 mg, such as 50 mg to 100 mg, such as 70 mg, wherein any of theforegoing amounts may be administered twice a day.

Effective doses will also vary, as recognized by those skilled in theart, depending on the diseases treated, the severity of the disease, theroute of administration, the sex, age and general health condition ofthe subject, excipient usage, the possibility of co-usage with othertherapeutic treatments such as use of other agents and the judgment ofthe treating physician.

For pharmaceutical compositions that comprise a second therapeuticagent, an effective amount of the second therapeutic agent is betweenabout 20% and 100% of the dosage normally utilized in a monotherapyregime using just that agent. Preferably, an effective amount is betweenabout 70% and 100% of the normal monotherapeutic dose. The normalmonotherapeutic dosages of these second therapeutic agents are wellknown in the art. See, e.g., Wells et al., eds., PharmacotherapyHandbook, 2nd Edition, Appleton and Lange, Stamford, Conn. (2000); PDRPharmacopoeia, Tarascon Pocket Pharmacopoeia 2000, Deluxe Edition,Tarascon Publishing, Loma Linda, Calif. (2000), each of which referencesare incorporated herein by reference in their entirety.

Methods of Treatment

In another embodiment, the invention provides a method of inhibiting amember of the Janus kinase (JAK) family of kinases in a cell, comprisingcontacting the cell with a compound of Formula I herein. In oneembodiment, the JAK kinase is JAK1. In one embodiment, the JAK kinase isJAK2.

According to another embodiment, the invention provides a method oftreating a disease or condition that may be treated by momelotinib. Suchdiseases include chronic myeloproliferative neoplasms (MPNs), primarymyelofibrosis (PMF), post-polycythemia vera (PV) or post-essentialthrombocythemia (ET).

Identifying a subject in need of such treatment can be in the judgmentof a subject or a health care professional and can be subjective (e.g.opinion) or objective (e.g. measurable by a test or diagnostic method).In one embodiment the subject is a patient.

In another embodiment, any of the above methods of treatment comprisesthe further step of co-administering to the subject in need thereof oneor more second therapeutic agents. The choice of second therapeuticagent may be made from any second therapeutic agent known to be usefulfor co-administration with momelotinib. The choice of second therapeuticagent is also dependent upon the particular disease or condition to betreated. Examples of second therapeutic agents that may be employed inthe methods of this invention are therapeutics useful in treating adisease selected from chronic myeloproliferative neoplasms (MPNs),primary myelofibrosis (PMF), post-polycythemia vera (PV) orpost-essential thrombocythemia (ET).

The term “co-administered” as used herein means that the secondtherapeutic agent may be administered together with a compound of thisinvention as part of a single dosage form (such as a composition of thisinvention comprising a compound of the invention and an secondtherapeutic agent as described above) or as separate, multiple dosageforms. Alternatively, the additional agent may be administered prior to,consecutively with, or following the administration of a compound ofthis invention. In such combination therapy treatment, both thecompounds of this invention and the second therapeutic agent(s) areadministered by conventional methods. The administration of acomposition of this invention, comprising both a compound of theinvention and a second therapeutic agent, to a subject does not precludethe separate administration of that same therapeutic agent, any othersecond therapeutic agent or any compound of this invention to saidsubject at another time during a course of treatment.

Effective amounts of these second therapeutic agents are well known tothose skilled in the art and guidance for dosing may be found in patentsand published patent applications referenced herein, as well as in Wellset al., eds., Pharmacotherapy Handbook, 2nd Edition, Appleton and Lange,Stamford, Conn. (2000); PDR Pharmacopoeia, Tarascon Pocket Pharmacopoeia2000, Deluxe Edition, Tarascon Publishing, Loma Linda, Calif. (2000),and other medical texts. However, it is well within the skilledartisan's purview to determine the second therapeutic agent's optimaleffective-amount range.

In one embodiment of the invention, where a second therapeutic agent isadministered to a subject, the effective amount of the compound of thisinvention is less than its effective amount would be where the secondtherapeutic agent is not administered. In another embodiment, theeffective amount of the second therapeutic agent is less than itseffective amount would be where the compound of this invention is notadministered. In this way, undesired side effects associated with highdoses of either agent may be minimized Other potential advantages(including without limitation improved dosing regimens and/or reduceddrug cost) will be apparent to those of skill in the art.

In yet another aspect, the invention provides the use of a compound ofFormula I alone or together with one or more of the above-describedsecond therapeutic agents in the manufacture of a medicament, either asa single composition or as separate dosage forms, for treatment in asubject of a disease, disorder or symptom set forth above. Anotheraspect of the invention is a compound of Formula I for use in thetreatment in a subject of a disease, disorder or symptom thereofdelineated herein.

EXAMPLES Example 1 Evaluation of Metabolic Stability

Microsomal Assay:

Human liver microsomes (20 mg/mL) are obtained from Xenotech, LLC(Lenexa, Kans.). β-nicotinamide adenine dinucleotide phosphate, reducedform (NADPH), magnesium chloride (MgCl₂), and dimethyl sulfoxide (DMSO)are purchased from Sigma-Aldrich.

Determination of Metabolic Stability:

7.5 mM stock solutions of test compounds are prepared in DMSO. The 7.5mM stock solutions are diluted to 12.5-50 μM in acetonitrile (ACN). The20 mg/mL human liver microsomes are diluted to 0.625 mg/mL in 0.1 Mpotassium phosphate buffer, pH 7.4, containing 3 mM MgCl₂. The dilutedmicrosomes are added to wells of a 96-well deep-well polypropylene platein triplicate. A 10 μL aliquot of the 12.5-50 μM test compound is addedto the microsomes and the mixture is pre-warmed for 10 minutes.Reactions are initiated by addition of pre-warmed NADPH solution. Thefinal reaction volume is 0.5 mL and contains 0.5 mg/mL human livermicrosomes, 0.25-1.0 μM test compound, and 2 mM NADPH in 0.1 M potassiumphosphate buffer, pH 7.4, and 3 mM MgCl₂. The reaction mixtures areincubated at 37° C., and 50 μL aliquots are removed at 0, 5, 10, 20, and30 minutes and added to shallow-well 96-well plates which contain 50 μLof ice-cold ACN with internal standard to stop the reactions. The platesare stored at 4° C. for 20 minutes after which 100 μL of water is addedto the wells of the plate before centrifugation to pellet precipitatedproteins. Supernatants are transferred to another 96-well plate andanalyzed for amounts of parent remaining by LC-MS/MS using an AppliedBio-systems API 4000 mass spectrometer. The same procedure is followedfor the non-deuterated counterpart of the compound of Formula I and thepositive control, 7-ethoxycoumarin (1 μM). Testing is done intriplicate.

Data Analysis:

The in vitro t_(1/2)s for test compounds are calculated from the slopesof the linear regression of % parent remaining (ln) vs incubation timerelationship.

in vitro t_(1/2)=0.693/k

k=−[slope of linear regression of % parent remaining (ln) vs incubationtime]

Data analysis is performed using Microsoft Excel Software.

Without further description, it is believed that one of ordinary skillin the art can, using the preceding description and the illustrativeexamples, make and utilize the compounds of the present invention andpractice the claimed methods. It should be understood that the foregoingdiscussion and examples merely present a detailed description of certainpreferred embodiments. It will be apparent to those of ordinary skill inthe art that various modifications and equivalents can be made withoutdeparting from the spirit and scope of the invention.

What is claimed is:
 1. A compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein: Y¹, Y², Y³, Y⁴,Z¹, Z², Z³, Z⁴, W¹ and W² are each independently selected from hydrogenand deuterium; provided that if Y¹, Y², Y³, Y⁴, Z¹, Z², Z³, Z⁴, and W¹are each hydrogen, then W² is deuterium.
 2. The compound of claim 1,wherein Y¹, Y², Y³ and Y⁴ are each hydrogen.
 3. The compound of claim 1,wherein Y¹, Y², Y³ and Y⁴ are each deuterium.
 4. The compound of claim1, wherein Z¹, Z², Z³ and Z⁴ are each hydrogen.
 5. The compound of claim1, wherein Z¹, Z², Z³ and Z⁴ are each deuterium.
 6. The compound ofclaim 1, wherein W¹ and W² are each hydrogen.
 7. The compound of claim1, wherein W¹ and W² are each deuterium.
 8. The compound of claim 1,wherein the compound is selected from any one of the compounds (Cmpd)set forth in Table 1 (below): TABLE 1 Y¹ = Y² = Z¹ = Z² = Cmpd # Y³ = Y⁴Z³ = Z⁴ W¹ = W² 101 H H D 102 H D H 103 H D D 104 D H H 105 D H D 106 DD H 107 D D D

or a pharmaceutically acceptable salt thereof, wherein any atom notdesignated as deuterium in Formula I is present at its natural isotopicabundance.
 9. The compound of claim 1, wherein any atom not designatedas deuterium is present at its natural isotopic abundance.
 10. Apharmaceutical composition comprising the compound of claim 1 or apharmaceutically acceptable salt thereof; and a pharmaceuticallyacceptable carrier.
 11. A method of treating a disease selected fromchronic myeloproliferative neoplasms (MPNs), primary myelofibrosis (PMF)post-polycythemia vera (PV) or post-essential thrombocythemia (ET),comprising administering to a subject in need of such treatment acompound of claim
 1. 12. A method of inhibiting a member of the MKfamily of kinases in a cell, comprising contacting the cell with acompound of claim
 1. 13. The compound of claim 2, wherein Z¹, Z², Z³ andZ⁴ are each hydrogen.
 14. The compound of claim 3, wherein Z¹, Z², Z³and Z⁴ are each hydrogen.
 15. The compound of claim 2, wherein Z¹, Z²,Z³ and Z⁴ are each deuterium.
 16. The compound of claim 3, wherein Z¹,Z², Z³ and Z⁴ are each deuterium.
 17. The compound of claim 2, whereinW¹ and W² are each hydrogen.
 18. The compound of claim 3, wherein W¹ andW² are each hydrogen.
 19. The compound of claim 4, wherein W¹ and W² areeach hydrogen.
 20. The compound of claim 5, wherein W¹ and W² are eachhydrogen.
 21. The compound of claim 1, wherein the deuteriumincorporation at each designated deuterium atom is at least 90%.
 22. Thecompound of claim 1, wherein the deuterium incorporation at eachdesignated deuterium atom is at least 95%.
 23. The compound of claim 1,wherein the deuterium incorporation at each designated deuterium atom isat least 97%.